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SummaryBackground Germ cell tumors (GCTs) are highly curable diseases; however, not all patients can be cured. Patients in their second relapse have especially poor prognoses. PD-L1 expression is significantly higher in GCTs than in normal testicular tissue, and high PD-L1 expression is associated with a poor prognosis. This study aimed to determine the efficacy and safety of avelumab, a PD-L1 inhibitor, in patients with GCTs. Methods In this phase 2 study, patients with multiple relapsed and/or refractory GCTs were treated with avelumab at a dose of 10 mg/kg administered biweekly until progression or unacceptable toxicity. The primary endpoint was 12-week progression-free survival (PFS). Fifteen evaluable patients had to be enrolled in the first cohort, and if <8 of 15 patients had 12-week PFS, the study was to be terminated. Here, we report the results of the first stage of the trial. Results From November 2017 to January 2018, 8 patients with a median age of 29 years (range, 22 to 52 months) were enrolled. Patients were pretreated with a median of 5 (range, 1 to 6) previous lines of platinum-based therapies; 5 tumors (62.5%) were absolutely refractory to cisplatin, and 5 patients (62.5%) had visceral nonpulmonary metastases. At a median follow-up period of 2.6 months (range, 0.3 to 14.4), all the patients experienced disease progression, and 7 patients (87.5%) died. The twelve-week PFS was 0%, median PFS was 0.9 months (95% CI 0.5–1.9), and median OS was 2.7 months (95% CI 1.0–3.3). Avelumab was well tolerated, and no severe adverse events were observed. Conclusions This study failed to achieve its primary endpoint. Our data suggest a lack of avelumab efficacy in unselected multiple relapsed/refractory GCTs.

In localized prostate cancer (PCa), Grade Group (GG) and Gleason Score (GS) have a well-established prognostic role. In metastatic castration resistant prostate cancer (mCRPC), the prognostic role of GS and GG is less defined. In first-line treatment of mCRPC, androgen receptor (AR)-directed drugs (abiraterone acetate, enzalutamide) and docetaxel represent the referring options. There is no evidence that the GS/GG systems can add information to guide the choice between AR-directed drugs and docetaxel in the first-line setting of mCRPC. Nowadays there are no validated biomarkers, which define patients who may benefit or not from hormonal treatments or chemotherapy. Androgen receptor (AR) copy number variations (CNV) are predictive factors of poor response to abiraterone and enzalutamide. There are no available data about the association between AR CNV and GG. In this retrospective study, we analysed the association of the highest GG score with AR CNV and their impact on the clinical outcome of AR-directed drugs and docetaxel as first-line therapy for mCRPC patients. Patients benefit from docetaxel, abiraterone or enzalutamide regardless the GG. However, the presence of GG5 and AR CNV gain identifies a subgroup of patients with poor prognosis, which could benefit from front-line docetaxel instead of AR-directed drugs.

The GOG240 trial established bevacizumab with chemotherapy as standard first-line therapy for metastatic or recurrent cervical cancer. In the BEATcc trial (ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030), we aimed to evaluate the addition of an immune checkpoint inhibitor to this standard backbone. In this investigator-initiated, randomised, open-label, phase 3 trial, patients from 92 sites in Europe, Japan, and the USA with metastatic (stage IVB), persistent, or recurrent cervical cancer that was measurable, previously untreated, and not amenable to curative surgery or radiation were randomly assigned 1:1 to receive standard therapy (cisplatin 50 mg/m2 or carboplatin area under the curve of 5, paclitaxel 175 mg/m2, and bevacizumab 15 mg/kg, all on day 1 of every 3-week cycle) with or without atezolizumab 1200 mg. Treatment was continued until disease progression, unacceptable toxicity, patient withdrawal, or death. Stratification factors were previous concomitant chemoradiation (yes vs no), histology (squamous cell carcinoma vs adenocarcinoma including adenosquamous carcinoma), and platinum backbone (cisplatin vs carboplatin). Dual primary endpoints were investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumours version 1.1 and overall survival analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03556839, and is ongoing. Between Oct 8, 2018, and Aug 20, 2021, 410 of 519 patients assessed for eligibility were enrolled. Median progression-free survival was 13·7 months (95% CI 12·3–16·6) with atezolizumab and 10·4 months (9·7–11·7) with standard therapy (hazard ratio [HR]=0·62 [95% CI 0·49–0·78]; p<0·0001); at the interim overall survival analysis, median overall survival was 32·1 months (95% CI 25·3–36·8) versus 22·8 months (20·3–28·0), respectively (HR 0·68 [95% CI 0·52–0·88]; p=0·0046). Grade 3 or worse adverse events occurred in 79% of patients in the experimental group and in 75% of patients in the standard group. Grade 1–2 diarrhoea, arthralgia, pyrexia, and rash were increased with atezolizumab. Adding atezolizumab to a standard bevacizumab plus platinum regimen for metastatic, persistent, or recurrent cervical cancer significantly improves progression-free and overall survival and should be considered as a new first-line therapy option. F Hoffmann-La Roche.

Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB–IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0–2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin–carboplatin, or 15 mg/kg every 21 days combined with gemcitabine–carboplatin or paclitaxel–carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4–9·3) in the standard chemotherapy group and 11·8 months (10·8–12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41–0·65; log-rank p<0·0001). Most common grade 3–4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. Hoffmann–La Roche and Associazione Italiana per la Ricerca sul Cancro.

Background: This study aimed to investigate copy number variations (CNVs) of CYP17A1 and androgen receptor ( AR ) genes in serum cell-free DNA collected before starting abiraterone in 53 consecutive patients with castration-resistant prostate cancer (CRPC). Methods: Serum DNA was isolated and CNVs were analysed for AR and CYP17A1 genes using Taqman copy number assays. The association between CNVs and progression-free/overall survival (PFS/OS) was evaluated by the Kaplan–Meier method and log-rank test. Results: Median PFS of patients with AR gene gain was 2.8 vs 9.5 months of non-gained cases ( P <0.0001). Patients with CYP17A1 gene gain had a median PFS of 2.8 months vs 9.2 months in the non-gained patients ( P =0.0014). A lower OS was reported in both cases ( AR : P <0.0001; CYP17A1 : P =0.0085). Multivariate analysis revealed that PSA decline ⩾50%, AR and CYP17A1 CNVs were associated with shorter PFS ( P <0.0001, P =0.0004 and P =0.0450, respectively), while performance status, PSA decline ⩾50%, AR CNV and DNA concentration were associated with OS ( P =0.0021, P =0.0014, P =0.0026 and P =0.0129, respectively). Conclusions: CNVs of AR and CYP17A1 genes would appear to be associated with outcome of CRPC patients treated with abiraterone.

Lichenoid reactions are one of the most frequently observed toxicities with anticancer agents and, recently, a rapid emergence of immunotherapies in oncology has hastened the need to better characterize their unique toxicity profiles, particularly for less common skin toxicities, including anogenital lichen sclerosus et atrophicus (LSA). This case series describes four patients with advanced cancer (one melanoma, two lung cancers, and one kidney tumor) developing LSA lesions while receiving an immunotherapy. Medical records from 2017 to 2020 were retrospectively reviewed. Two patients received pembrolizumab, anti-programmed cell death-1 (PD-1), one nivolumab, anti-programmed cell death-1 (PD-1), and one ipilimumab, an immune checkpoint inhibitor. LSA emerged after a median of 3 months (range, 2–4 months) from starting immunotherapy. All LSA cases were grade 2. Three cases occurred on the penis and one case on the anus. All patients improved after a specific treatment for LSA, and no LSA-related antineoplastic treatment interruption/life-threatening condition were reported. To date, this is the first case series of LSA lesions associated with immunotherapy. Early LSA recognition and management is helpful in cancer patients on immunotherapy allowing a long survival and treatment response.

Background: Everolimus is a mammalian target of rapamycin inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). We aimed to assess the association between pre-treatment neutrophil-to-lymphocyte ratio (NLR) and the outcome of patients treated with everolimus for mRCC. Methods: Ninety-seven patients with mRCC were treated with everolimus till April 2013 in our institutions. Patients were stratified in two groups with NLR >3 (Group A) vs <3 (Group B). Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier method. Gender, age, Motzer prognostic group, PFS on first-line therapy, neutrophilia and NLR were included in the Cox analysis to investigate their prognostic relevance. Results: Median OS and PFS were 10.6 and 5.3 months, respectively. Median OS was 12.2 months in Group A and 24.4 months in Group B ( P =0.001). Median PFS was 3.4 months in Group A and 9.9 months in Group B ( P <0.001). At multivariate analysis, only Motzer prognostic group and NLR were independent prognostic factors for OS and PFS. Conclusion: Pre-treatment NLR is an independent prognostic factor for patients with mRCC treated with second- or third-line everolimus. This should be investigated and validated in prospective studies.

Background Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era. Methods We investigated the Meet-URO-15 study dataset of 571 pretreated mRCC patients receiving nivolumab as second or further lines about the prognostic role of the previous nephrectomy (received in either the localized or metastatic setting) in the overall population and according to the Meet-URO score groups. Results Patients who underwent nephrectomy showed a significantly reduced risk of death (HR 0.44, 95% CI 0.32–0.60, p  < 0.001) with a longer median overall survival (OS) (35.9 months vs 12.1 months), 1-year OS of 71.6% vs 50.5% and 2-years OS of 56.5% vs 22.0% compared to those who did not. No significant interaction between nephrectomy and the overall five Meet-URO score risk groups was observed ( p  = 0.17). It was statistically significant when merging group 1 with 2 and 3 and group 4 with 5 ( p  = 0.038) and associated with a longer OS for the first three prognostic groups ( p  < 0.001), but not for groups 4 and 5 ( p  = 0.54). Conclusions Our study suggests an overall positive impact of the previous nephrectomy on the outcome of pretreated mRCC patients receiving immunotherapy. The clinical relevance of cytoreductive nephrectomy, optimal timing and patient selection deserves further investigation, especially for patients with Meet-URO scores of 1 to 3, who are the once deriving benefit in our analyses. However, that benefit is not evident for IMDC poor-risk patients (including the Meet-URO score groups 4 and 5) and a subgroup of IMDC intermediate-risk patients defined as group 4 by the Meet-URO score.

PurposeTo evaluate the clinical value of 68Ga-PSMA PET/CT negativity in patients with biochemical recurrent prostate cancer (BCR).MethodsOne hundred three BCR patients (median age, 70 years; median PSA, 0.47 ng/mL) with negative 68Ga-PSMA PET/CT, followed up for at least 1 year, were retrospectively identified in a database of 1003 consecutive patients undergoing 68Ga-PSMA PET/CT for BCR. Clinical recurrence (CR) was determined or excluded on follow-up imaging selected as per clinical practice. Clinical recurrence-free survival (CRFS) was computed from the date of negative 68Ga-PSMA PET/CT to the date of evident disease; frequencies of CRFS were described as per ISUP patient subset (subset 1: ISUP grades 1 and 2; subset 2: ISUP grade 3; subset 3: ISUP grades 4 and 5) and other conventional variables.ResultsIn 57 patients out of 103 (55.3%), CR was detected in the prostatic fossa (45.6%), nodes (38.6%), and bone (15.8%). The median CRFS was 15.4 months (range, 12.1–20.5), with a CRFS at 12 months in 61.4% of cases (range, 50.9–70.4) whereas the 24-month CRFS was 34.8% (range, 24–45.8). ISUP subset 1 benefited from significantly longer CRFS compared to subset 2 and subset 3 (median CRFS, 20.5 months, 12.6 months, and 12.1 months, respectively). ISUP subset 3 had significantly poorer 24-month CRFS (9.3%) compared to subset 1 (47.8%) and subset 2 (33.5%). At the univariate and multivariate analyses, the ISUP subset was the only significant risk factor for clinical relapse; ISUP subset 3 and subset 2 patients held a higher risk of CR compared to subset 1 patients (HR of 2.75 [1.35–5.57] for subset 3 versus subset 1; HR of 2.08 [1.11–3.88] for subset 2 versus subset 1).Conclusion68Ga-PSMA PET/CT negativity in early BCR patients (PSA < 0.5 ng/mL) with low-grade primary prostate cancer (ISUP1 and 2) may support the exploration of a clinical surveillance approach in future prospective studies.